4-Halo-3-Hydroxyanthranilates are Potent Inhibitors of 3-Hydroxyanthranilate Oxygenase in the Rat Brain in Vitro and in Vivo

Abstract

3-Hydroxyanthranilic acid oxygenase (3HA0; E.C. 1.13.11.6) is the enzyme responsible for the metabolism of 3-hydroxyanthranilic acid (3HANA) to α-amino-β-carboxymuconic acid-w-semialdehyde, which in turn spontaneously rearranges to form the endogenous excitotoxin quinolinic acid (QUIN). Since increased levels of QUIN can trigger the structural deterioration of nerve cells, it has been implicated in the etiology of neurodegenerative diseases (Schwarcz et al., 1984). It follows that specific inhibitors of 3HAO may be of therapeutic value in diseases which can be traced to an overabundance of QUIN. 4-Chloro-3-hydroxyanthranilic acid (4-C1-3HANA), originally described by Parli et al. (1980), is a very effective blocker of 3HAO, and therefore can serve as a lead compound in the development of novel 3HAO inhibitors. The present study was designed to compare the inhibitory potency of 4-C1-3HANA with that of 4-Br- and 4-F-3HANA in cell free homogenates of rat brain, and to evaluate the effectiveness of 3HAO inhibition in vivo by microdialy-sis using the most potent compound discovered so far (4-Br-3HANA).